Pharmaceutical Substances Syntheses, Patents, Applications - Part 3 doc

20 mg; eye drops 1 % Trade Names: D: Miochol-E CIBA Vision J: Acetylcholine Roche I: Farmigea acetilcolina Neucholin-A Zeria; wfm Farmigea; wfm Ovisot Daiichi; wfm... numerous combinati

Acetylcholine chloride A 2 1

hydroxide

RN: 56-13-3 MF: C,H,,NO, MW: 163.22

bromide

RN: 66-23-9 MF: C,H,,BrNO, MW: 226.1 1 EINECS: 200-622-4

LD,,,: 170 mglkg (M, s.c.)

trimethyl- 2-chloro- choline Acetylcholine chloride

arnine (I) ethanol (11) chloride (In)

O H -

I + 8 + H ~ C \ + f i ~ ~ 4 111 -+

H,c/~\

C H 3 ethylene choline

oxide hydroxide

I + + ( Acetylcholine chloride I

Reference(s);

Baeyer, A v.: Justus Liebigs Ann Chem (JLACBF) 142, 235 (1867)

Nothnagel: Arch Pharm (Weinheim, Ger.) (ARPMAS) 232,265 (1894)

Fourneau, E.; Page, H.J.: Bull Soc Chim Fr (BSCFAS) [4] 15,544 (1914)

DE 801 210 (BASF; appl 1948)

US 1 957 443 (Merck & Co.; 1934; appl 1931)

US 2 012 268 (Merck & Co.; 1935; appl 1931)

US 2 013 536 (Merck & Co.; 1935; appl 1931)

Formulation(s): amp 20 mg; eye drops 1 %

Trade Name(s):

D: Miochol-E (CIBA Vision) J: Acetylcholine (Roche)

I: Farmigea acetilcolina Neucholin-A (Zeria); wfm

(Farmigea); wfm Ovisot (Daiichi); wfm

22 A Acetylcysteine

Use: mucolytic agent RN: 616-91-1 MF: C5H9N03S MW: 163.20 EINECS: 210-498-3

LD,,,: 400 mglkg (M, i.p.); 3800 mglkg (M, i.v.); 7888 mglkg (M, p.0.):

1 140 mglkg (R, i.v.); 5050 mglkg (R, p.0.);

700 mglkg (dog, i.p.1; 700 mg/kg (dog, i.v.); >1 g/kg (dog, p.0.)

CN: N-acctyl-L-cysteine

monosodium salt

RN: 19542-74-6 MF: C,H,NNaO,S MW: 185.18 EINECS: 243-143-6

LD,,,: 3800 mglkg (M, i.v.);

2559 mglkg (R,i.v.)

monoammonium salt

RN: 50807-78-8 MF: C,H,NO,S H,N MW: 180.23

HCI 0 0 CH3COONo

L-cysteine acetic anhydride

hydrochloride

monohydrate

Acdylcysteine I

Keference(s):

US 3 091 569 (Mead Johnson; 28.5.1963; appl 26.8.1960)

US 3 184 505 (Mead Johnson; 18.5.1965; ap$ 18.6.1962)

Smith, H.A.; Gorin, G.: J Org Chem (JOCEAH) 26,820 (1961)

ammonium sulf (mucolysis of bronchial mucus by nebulization):

DOS 2 305 271 (Bristol-Myers; appl 2.2.1973; USA-prior 3.2.1972)

Formulation(s): amp 300 mg (as monosodium salt); cps 200 mg; eff tabl 100 mg, 200 mg, 600 mg; f c tabl

100 mg, 200 mg, 600 mg; gran 10 mg, 100 mg 200 mg, 600 mg; lyo for syrup I00 mg; syrup

200 mg1lO ml; tabl I00 mg, 200 mg, 600 mg

Trade Name(s):

D: ACC (Hexal)

Acemuc (betapharm)

Fluimucil-1001-200

(Zambon)

Rinofluimucil (1npharzam)-

comb

numerous combination and

generic preparations

F: Broncoclar (Oberlin)

Codotussyl (Whitchall)

Euronac (Europhta)

Exomuc (Bouchara)

Fluimucil (Zambon) Fluimucil Antibiotic 750 (Zambon)

Gcnac (GCnCvrier) Mucolator (Abbott) Mucomyst (Bristol-Myers Squibb)

Mucothiol (SCAT) Rhinofluimucil (D6bat)- comb

Solmucol (GCnCvrier) Tixair (Byk)

GB: Iluhe (Alcon)-comb Parvolex (Evans) I: Brunac (Bruschettini) Fluimucil (Zambon) Mucisol (Deca) Rinofluimucil (Zambon) comb

J: Acetein (Senju) Mucofilin Sol (Eisai) USA: Mucosit (Dey)

Acetyldigitoxin A 23

Use: cardiotonic, cardiac glycoside RN: 11 11 -39-3 MF: C43HM0,4 M W : 806.99 EINECS: 214-178-4

LD,,,: >30 mg/kg (g p., p.0.);

514 pdkg (cat, i.v.); 250 pglkg (cat, p.0.)

CN: (3~,5~)-3-[(0-3-O-acetyl-2,6-dideoxy-~-~-ribo-hexopyranosy-(1+4)-0-2,6-dideoxy-~-~-ribo-

hexopyranosyl-(1 -14)-2,6-dideoxy-P-D-ribo-hexopyranosyl)oxy]- 14-hydroxycard-20(22)-enolide

H

enzymatic hydrolysis digilanidase

OH OH lonatoside A

Acetyldigitoxin

u

K Acetyldigitoxin

0

H3C-

0 r C ~ 3 THF TosOH

H,C+O O-CH,

digitoxin triethyl

orthoocetote

a Stoll, A et a].: Helv Chim Acta (HCACAV) 34,397 (1951)

Gisvold, 0 : J Pharm Sci (JPMSAE) 61, 1320 (1972)

HU 155 716 (Richter Gedeon; appl 20.1.1968)

DE 925 047 (Sandoz; appl 1954; CH-prior 1952)

b DE 2 01 0 422 (Boehringer Ing.; appl 5.3.1970)

alternative synthesis:

DE 2 206 737 (Boehringer Mannh.; appl 12.2.1972) (a-Acetyldigoxin, q v.)

Formulation(s): tabl 0.2 mg

Trade Name(s):

D: Acylanid (Sandoz); wfm F: Acylanid (Sandoz); wfm USA: Acylanid (Sandoz); wfm

ATC: C01AA02 Use: cardiotonic, cardiac glycoside RN: 551 1-98-8 MF: C4311hh015 MW: 822.99 EINECS: 226-855-1

LD,,,: 3300 vg/kg(g p., p.0.);

200 vg/kg (cat, p.0.)

CN: (3~,5~,12~)-3-[(0-3-0-acetyl-2,6-dideoxy-~-~-ribo-hexopyranosy-(+4)-0-2,6-dideoxy-~-~-ribo-

hexopyranosyl-(I +4)-2,6-dideoxy-P-D-ribo-hexopyranosyl)oxy]- 12,14-dihydroxycard-20(22)-enolide

digilanidose

ocetyldigitoxin partition of the methonol

+ solution between digilonide enzymatic hydrolysis , - acetyldigoxin Hz0 Ond CHC13

+

(lonotoside A B C) acetylgitoxin

2 HCOOH

1 dimethyl sulfate

2 formic acid

OH digoxin sodium acetate

Reference(s):

a Fieser, L.F.; Fieser, M.: Steroide, p 801, Verlag Chemie, Weinheim 1961

b GB 1 162 614 (Heilmittelwerke Wien; appl 1.2.1968; A-prior 7.2.1967)

Gisvold, 0 : J Pharm Sci (JPMSAE) 61, 1320 (1972)

alternative syntheses:

DE 2 010 422 (Boehringer Ing.; appl 5.3.1970) (Acetyldigitoxin, q v.)

Rietbrock, N.; Kuhlmann, J.: Naunyn-Schmiedeberg's Arch Pharmacol (NSAPCC) 279,413 (1973)

Formulation(s): sol 0.5 mglml; tabl 0.25 mg, 0.2 mg

Trade Name(s):

D: Card-Hydergin (Sandoz)- Lanadigin (Promonta); Nitro-Sandolanid (Sandoz)-

Digi-Complamin Lanadigin EL (Promonta); Sandolanid (Sandoz)

(Promonta)-comb.; wfm

ATC: COIAA02 Use: cardiotonic, cardiac glycoside RN: 5355-48-6 MF: C,,H,O1, MW: 822.99 EINECS: 226-337-5

LD,,: 2400 kg/kg (g, p., p.0.);

422 !%kg (dog, p.o.1

CN: (3~,5~,12~)-3-[(0-4-0-acetyl-2,6-dideoxy-[oxy-~-~-ribo-

hexopyranosyl-(l~4)-2,6-dideoxy-~-~-ribo-hexopyranosyl)oxy]- 12,14-dihydroxycard-20(22)-enolide

dicyclohexyl- carbodiimide

a Hopponen, R.E.; Gisvold, 0 : J Am Pharm Assoc (JPHAA3) 41, 146 (1952)

Rangaswami, S et al.: Indian J Pharm (IJPAAO) 17,253 (1955)

b HU 7 147 (Richter Gedeon; appl 5.6.1972)

alternative syntheses:

Haberland, G.: Arzneim.-Forsch (ARZNAD) 15,481 (1965)

Graf, E.; Pfaff, J.: Arch Pharm (Weinheim, Ger.) (ARPMAS) 307,943 (1974)

DOS 2 826 532 (LEK tovarna farm.; appl 16.6.1978; YU-prior 22.6.1977)

medical use:

DOS 1 921 307 (Boehringer Ing.; appl 25.4.1969) addition to DOS 1 767 553

Formulation(s): tabl 0.1 mg, 0.2 mg

Trade Name(s):

Beta-Acetyldigoxin R.A.N (ratiopharm) Digox (ct-Arzneimittel)

= glycotop (R.A.N.) Digostada 0.21-mite Digoxin-Didier

Digostade (Stada) Gladixol (Corax)

28 A Acetylsalicylic acid

Kardiamed (Medice) numerous combination Cardioreg (Nattermann);

Stillacor (Wolff) I: Beta-Acigoxia (Inverni

della Beffa); wfm

Acetylsalicylic acid

(Acidum acetylsalicylicum; Aspirin)

ATC: AOlADO5; B01 ACO6; M01BA03; N02BA01; N02BA5 1

Use: analgesic, antipyretic, antirheumatic, platelet aggregation inhibitor RN: 50-78-2 MF: CyH,04 MW: 180.16 EINECS: 200-064-1

LD,,: 280 mglkg (M, i.p.); 250 m g k g (M, p.0.); 1520 m g k g (M, s.c.);

340 mglkg (R, i.p.); 200 mgkg (R, p.0.); 1600 mglkg (R, s.c.);

1075 m g k g (g p., p.0.);

1010 m g k g (rabbit, p.0.);

681 mglkg (dog, i.v.); 700 mglkg (dog, p.0.)

CN: 2-(acety1oxy)benzoic acid

aluminum salt

RN: 147-31-9 MF: C27H2,A10,2 MW: 564.44

calcium salt

RN: 69-46-5 MF: Cl,H14Ca0, MW: 398.38 EINECS: 200-707-6

lithium salt

RN: 552-98-7 MF: CyH7Li04 MW: 186.09 EINECS: 209-029-5

sodium salt

RN: 493-53-8 MF: CyH7Na04 MW: 202.14 EINECS: 207-777-7

LD,,: 730 mglkg (M, i.p.);

1450 m g k g (R, i.p.)

magnesium salt

RN: 132-49-0 MF: C18H14Mg0, MW: 382.61 EINECS: 205-062-4

LD,,: 620 mglkg (M, s.c.)

lysine salt (1:l)

RN: 62952-06-1 MF: CyH,04 C,H,4N202 MW: 326.35

LD,,: 950 m g k g (M, i.v.); 3270 m g k g (M, p.0.);

1525 m g k g (R, i.v.); 4350 m g k g (R, p.0.)

salicylic acetic anhydride 1 Acetylsalicylic acid

acid

Reference(s):

Ullmanns Encykl Tech Chem., 3 Aufl., Vol 13,90

US 3 235 583 (Norwich Pharmacal; 15.2.1966; appl 22.7.1964)

acetylation in presence of pyridine for avoidance of formation of acetylsalicylic anhydride and

acetylsalicylsalicylic acid:

DOS 2 635 540 (A L de Week, H Bundgaard; appl 6.8.1976)

acetylation in presence of H,SO,:

US 2 731 492 (J Kamlet; 1956; appl 1954)

crystallization:

US 2 890 240 (Monsanto; 1959; appl 1957)

Acetylsulfafurazole A 29

DRP 585 986 (Chinoin; appl 1931 ; H.-prior 193 I)

US 2 698 332 (Reheis Comp.; 1954; appl 1951)

US 2 918 485 (Keystone Chemurgic Corp.; 1959; appl 1955)

GB 888 666 (Hardman & Holden; appl 1959)

aluminum acetylsalicylate glutaminate:

DOS 2 909 829 (Kyowa Hakko; appl 13.3.1979; J-prior 13.3.1978)

Trade Name(s):

D: Alka-Seltzer (Bayer)

Aspirin (Bayer; 1899)

Aspisol (Bayer; as DL-

lysine salt)

Aspro (Roche Nicholas)

ASS Dura (durachemie)

ASS-ratiopharm

(ratiopharm)

Godamed (Pfleger)

Micristin (OPW)

Miniasal (OPW)

Romigal (Romogal-Werk)

Santasal (Merckle)

numerous combination

preparations

F: Actron (Bayer)-comb

Afebry (Ga1ephar)-comb

Alka-Seltzer (Bayer)-comb

Antigrippine (SmithKline

Beecham)-comb

AspCgic 500 (SynthClabo;

as lysine salt)

Aspirine BayCr (Bayer) I:

Aspirine duRh6ne (Bayer) -

Aspirine pH 8 (3M SantC)

Aspirine Upsa (UPSA)

Aspirine Upsa Vitamine C

(UPSA)-comb

Aspirine Vitamine C (0berlin)-comb

Aspirisucre (Arkomedika) Aspro (Nicholas) Catalgine (Schwarz) Claragine (Nicholas) KardCgic (SynthClabd) Rhonal (Thtraplix) SargCpirine (ASTA Mtdica)

Solupsan (UPSA) numerous combination preparations

Angettes (Bristol-Myers) Aspan (Hoechst)-comb

Aspirin (Bayer) Caprin (Sinclair) Disprin CO (Reckitt &

Colman) Nu-Seals Aspirin (Lilly) Post MI (Ashbourne) numerous combination preparations

Ac Acsal (Formulario Naz.;

Tariff Nazionale; Scfm;

Iema; Farmacologico Milanese)

Acesal (Geymonat)

Alupir (Farmacologico Milanese; as aluminum salt)

Aspergum (Farmades) Aspirina (Bayer) Aspirinetta (Bayer) Aspro (Roche) Bufferin (Bristol-Myers Squibb)

Cemirit (Bayer) Endydol (Guidotti) Kilios (Carlo Erba) numerous combination preparations

J: generic preparations USA: Acuprin (Richwood) Ecotrin (SmithKline Beecham Consumer) Equagesic (Wyeth-Ayerst) Fiorinal (Novartis) Halfprin (Kramer) Norgeric (3M) Percotan (Endo) Roboxisal (Robins)

(Acetylsulfisoxazole; Sulfisoxazole Acetyl) Use: antibacterial

RN: 80-74-0 MF: C,,H,,N,O,S MW: 309.35 EINECS: 201-305-3

I CN: N-[(4-aminophenyl)sulfonyl]-N-(3,4-dimethyl-5-isoxazolyl)acetamide

30 A Acexamic acid

sulfafurazole acetic anhydride

(4 v.)

C H ~ 2.3 Z oq NH,, 0 "C

H2N

Reference(s):

US 2 721 200 (Roche; 1955; appl 1953)

y

H2N

Formulation(s): susp 500 mg/5 ml

Trade Name(s):

USA: Eryzole (Alra)

Acetylsulfofurozole

Pediazole (Ross)

Acexamic acid

(Acide acexamique)

ATC: D03A Use: antifibrinolytic RN: 57-08-9 MF: C8H,,N03 MW: 173.21 EINECS: 200-310-8

CN: 6-(acety1amino)hexanoic acid

sodium salt

RN: 7234-48-2 MF: C,H,,NNaO, MW: 195.19 EINECS: 230-635-0

N-acetyl-c- coprolactarn

Reference(s):

Offe, H.A.: Z Naturforsch., B: Anorg Chem., Org Chem., Biochem., Biophys., Biol (ZENBAX) 2, 182 (1947) FR-M 2 332 (Rowa; appl 1963)

Acexamic acid

Formulation(s): amp 5 g (as sodium salt); cps 300 mg (as zinc salt); ointment 5 % (as sodium salt);

susp 300 mg (as zinc salt)

( q v.)

Trade Name(s):

F: PlastCnan (Isopharm) PlastCnan NComycine I: Plastenan (Italfarmaco);